Cystic Fibrosis
Conditions
Keywords
IV Gallium, Gallium, Ganite, Cystic Fibrosis, Gallium Infusion
Brief summary
The purpose of this research study is to test the pharmacokinetics, safety, and tolerability of an intravenous infusion of a drug called Ganite (gallium nitrate) in patients with cystic fibrosis. We want to see this drug is safe and tolerable and to see if high levels of the drug are found in the sputum. Funding Source - Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD)
Detailed description
This is a two center pharmacokinetic and safety dosing study of IV gallium nitrate (Ganite®) in cystic fibrosis (CF) patients. Eighteen subjects are planned. Each subject will be administered a single 5-day infusion of study medication (one of 2 doses). No placebo is used. Each subject will receive 5 days of continuous infusion of the experimental treatment. There will be two dosing cohorts (cohort 1: 100 mg/m2/day and cohort 2: 200 mg/m2/day). Cohort 2 will begin enrollment only after Data Safety Monitoring Committee (DSMC) safety review and approval of cohort 1 data. Study visits occur at baseline (day 1), day 3 (visit 2), day 6 (visit 3), day 8 (visit 4), day 14 (visit 5), day 28 (visit 6), and day 56 (visit 7). Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria and none of the exclusion criteria will be entered into the study. The following treatment regimens will be used: • Experimental treatment continuous infusion of gallium nitrate at the following doses cohort 1: 100 mg/m2/day and cohort 2: 200 mg/m2/day All subjects who receive at least one dose of study medication will be considered evaluable for safety and efficacy analyses. Incidence of adverse events will be monitored during the trial. Primary endpoints will be assessment of pharmacokinetic and safety/tolerability data. Secondary efficacy assessments will be based on changes in lung function and sputum P. aeruginosa density in sputum. Total duration of subject participation will be five weeks. Total duration of the study is expected to be 20 months.
Interventions
DRUG100 mg/m2 dose
5 day infusion of gallium nitrate (IV Ganite®) at a dose of 100 mg/m2/day
DRUG200 mg/m2 dose
5 day infusion of gallium nitrate (IV Ganite®) at 200 mg/m2/day
Sponsors
Cystic Fibrosis Foundation
University of Washington
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Adult male or female, between 18 and 55 years of age 2. Documented chronic colonization with Pseudomonas Aeruginosa (Pa) 3. Confirmed diagnosis of CF: 1. Documented history of \> 60 mmol/L chloride concentration in pilocarpine sweat chloride test And/Or 2. Genotype with two identifiable mutations consistent with CF, accompanied by one or more phenotypic features consistent with diagnosis of CF 4. Forced expiratory volume in the first second (FEV1) ≥ 30% of predicted value 5. Able to expectorate sputum 6. Serum liver function tests ≤ 2.5 x upper limit of normal 7. Serum urea nitrogen (BUN) and creatinine ≤ 1.5 x upper limit of normal 8. Serum creatinine ≤ 2.0 mg/dl 9. Hemoglobin ≥ 9 g/dl, platelets ≥ 100,000/mm3, and white blood cells (WBC) ≥ 4,500/mm3 and ≤ 15,000/mm3 10. Ionized calcium ≥ the lower limit of normal 11. Able to understand and sign the informed consent document, communicate with the Investigator, and comply with the requirements of the protocol 12. If female and of childbearing potential, must have a negative pregnancy test on Day 1 prior to receiving study drug 13. If female and of childbearing potential, is willing to use adequate contraception, as determined by the investigator, for the duration of the study
Exclusion criteria
1. Acute pulmonary exacerbation requiring antibiotic intervention within 2 weeks prior to screening 2. Osteoporosis defined as the most recent dexa scan within the prior 5 years with a T-score ≤ -2.5 3. Pregnant or lactating female 4. Known sensitivity to gallium 5. Use of biphosphonates 6. Use of any investigational drug and/or participated in any clinical trial within 3 months prior to screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Assessment of a 5 Day Infusion of Gallium Nitrate (IV Ganite®) | Day 1 at t=1, 2 and 6 hours, Day 3, Day 6 at t= 1, 2, 8, and 12, Day 14 and Day 28 | To assess the summed area under the curves of a 5 day infusion of IV Ga from day 1 to day 28 at two doses: 100 mg/m2/day in adult subjects with CF; 200 mg/m2/day in adult subjects with CF. To assess the safety of a 5 day infusion of IV Ga at two doses: 100 mg/m2/day in adult subjects with CF; 200 mg/m2/day in adult subjects with CF. Safety and tolerability of 5 days of treatment with IV administered gallium nitrate (IV Ganite®) at a doses of 100 mg/m2/day and 200 mg/m2/day. |
| Number of Serious Adverse Events | 56 days from starting dose | Safety as measured by serous adverse events |
| Number of Events When Study Drug Infusion Was Stopped Early | 6 days from starting dose | Tolerability as measured by adverse events of a 5 day continuous infusion of IV Gallium as assessed by stopping study drug infusion |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Spirometry From Baseline to Day 56 | 56 days from starting dose | Change in lung function as measured by FEV1 in liters from baseline to day 56 |
| Change in Spirometry as Measured by FVC From Baseline to Day 8 | 8 days from starting dose | Change from baseline in lung function assessed by FVC in liters after treatment with IV Ga at day 8 |
| Change in Spirometry From Baseline to Day 8 | 8 days | Change in spirometry as measured by FEV1 in liters from baseline to day 8 |
| Change in Sputum P. Aeruginosa Density From Baseline to Day 15 | 15 days from starting dose | Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 15 |
| Change in P. Aeruginosa Density From Baseline to Day 56 | 56 days from starting dose | Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 56 |
| Change in P. Aeruginosa Density From Baseline to Day 8 | 8 days from starting dose | Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 8 |
| Change in Lung Function From Baseline to Day 15 | 15 days from starting dose | Change in FEV1 in liters from baseline to day 15 |
| Change in Spirometry From Baseline to Day 28 | 28 days from starting dose | Change in lung function as measured by FEV1 in liters from baseline to day 28 |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited in the Adult cystic fibrosis clinics at 3 centers (the University of Washington, University of Iowa, John's Hopkins University) from the second quarter 2010 and closed February 1, 2012. The study had two dosing cohorts. Cohort 1 completed enrollment in February, 2011. Cohort 2 completed enrollment on February 1, 2012.
Pre-assignment details
We employed no run-in period. No subjects withdrew after randomization.
Participants by arm
| Arm | Count |
|---|---|
| IV Gallium (Ganite®) Infusion Five day continuous IV Gallium (Ganite®)infusion
IV Gallium Nitrate (Ganite®) infusion: 5 day infusion of gallium nitrate (IV Ganite®) at a doses of 100 mg/m2/day and 200 mg/m2/day and 5 day infusion of gallium nitrate (IV Ganite®) 100 mg/m2/day and 200 mg/m2/day | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | IV Gallium (Ganite®) Infusion |
|---|---|
| Age, Continuous | 32.8 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Forced expiratory volume in one second (FEV1) (in liters) | 2.25 liters |
| Forced vital capacity (FVC)(in liters) | 3.60 liters |
| Mean Pseudomonas aeruginosa quantitative sputum culture (CFU's/gr of sputum) | 116.7 Million CFU/gr of sputum |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 18 / 20 |
| serious Total, serious adverse events | 0 / 20 |
Outcome results
Primary
Number of Events When Study Drug Infusion Was Stopped Early
Tolerability as measured by adverse events of a 5 day continuous infusion of IV Gallium as assessed by stopping study drug infusion
Time frame: 6 days from starting dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Number of Events When Study Drug Infusion Was Stopped Early | 0 Number of times study drug interupted |
Primary
Number of Serious Adverse Events
Safety as measured by serous adverse events
Time frame: 56 days from starting dose
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Number of Serious Adverse Events | 0 Serious Adverse Events |
Primary
Pharmacokinetic Assessment of a 5 Day Infusion of Gallium Nitrate (IV Ganite®)
To assess the summed area under the curves of a 5 day infusion of IV Ga from day 1 to day 28 at two doses: 100 mg/m2/day in adult subjects with CF; 200 mg/m2/day in adult subjects with CF. To assess the safety of a 5 day infusion of IV Ga at two doses: 100 mg/m2/day in adult subjects with CF; 200 mg/m2/day in adult subjects with CF. Safety and tolerability of 5 days of treatment with IV administered gallium nitrate (IV Ganite®) at a doses of 100 mg/m2/day and 200 mg/m2/day.
Time frame: Day 1 at t=1, 2 and 6 hours, Day 3, Day 6 at t= 1, 2, 8, and 12, Day 14 and Day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Pharmacokinetic Assessment of a 5 Day Infusion of Gallium Nitrate (IV Ganite®) | 503 ug*hr/mL | Standard Deviation 98 |
| IV Gallium (Ganite®) Infusion 200 mg/m2/Day | Pharmacokinetic Assessment of a 5 Day Infusion of Gallium Nitrate (IV Ganite®) | 537 ug*hr/mL | Standard Deviation 153 |
Secondary
Change in Lung Function From Baseline to Day 15
Change in FEV1 in liters from baseline to day 15
Time frame: 15 days from starting dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in Lung Function From Baseline to Day 15 | 0.13 liters | Standard Deviation 0.17 |
Secondary
Change in P. Aeruginosa Density From Baseline to Day 56
Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 56
Time frame: 56 days from starting dose
Population: All available specimens
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in P. Aeruginosa Density From Baseline to Day 56 | -76.0 colony counts in millions per gm sputum | Standard Deviation 58.3 |
Secondary
Change in P. Aeruginosa Density From Baseline to Day 8
Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 8
Time frame: 8 days from starting dose
Population: All available specimens
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in P. Aeruginosa Density From Baseline to Day 8 | 21.1 colony counts in millions per gm sputum | Standard Deviation 297.5 |
Secondary
Change in Spirometry as Measured by FVC From Baseline to Day 8
Change from baseline in lung function assessed by FVC in liters after treatment with IV Ga at day 8
Time frame: 8 days from starting dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in Spirometry as Measured by FVC From Baseline to Day 8 | 0.16 liters | Standard Deviation 0.2 |
Secondary
Change in Spirometry From Baseline to Day 28
Change in lung function as measured by FEV1 in liters from baseline to day 28
Time frame: 28 days from starting dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in Spirometry From Baseline to Day 28 | 0.10 liters | Standard Deviation 0.14 |
Secondary
Change in Spirometry From Baseline to Day 56
Change in lung function as measured by FEV1 in liters from baseline to day 56
Time frame: 56 days from starting dose
Population: all those subjects enrolled after the amendment to add a day 56 (ITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in Spirometry From Baseline to Day 56 | 0.12 liters | Standard Deviation 0.19 |
Secondary
Change in Spirometry From Baseline to Day 8
Change in spirometry as measured by FEV1 in liters from baseline to day 8
Time frame: 8 days
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in Spirometry From Baseline to Day 8 | 0.13 liters | Standard Deviation 0.18 |
Secondary
Change in Sputum P. Aeruginosa Density From Baseline to Day 15
Change in sputum microbiology (specifically P. aeruginosa density based on quantitative cultures) from baseline to day 15
Time frame: 15 days from starting dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IV Gallium (Ganite®) Infusion 100 mg/m2/Day | Change in Sputum P. Aeruginosa Density From Baseline to Day 15 | -5.5 colony counts in millions per gm sputum | Standard Deviation 217.9 |